Crystal modification d of 8-cyano-1-cyclopropyl-7-(1s, 6s- 2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid

ABSTRACT

The present invention relates to a defined crystal modification of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, to processes for its preparation and to its use in pharmaceutical preparations.                    
     The crystal modification can be distinguished from other crystal modifications of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (I) by its characteristic X-ray powder diffractogram and its differential thermodiagram (see description).

The present invention relates to a defined crystal modification of8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, to processes for its preparation and to its use in pharmaceuticalpreparations.

Hereinbelow,8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of the formula (I) is referred to as CCDC.

CCDC is known from DE-A 19 633 805 or PCT Appl. No. 97 903 260.4.According to these publications, it is prepared by reacting7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid with (1S,6S)-2,8-diazabicyclo[4.3.0]nonane in a mixture ofdimethylformamide and acetonitrile in the presence of an auxiliary base.Water is added to the mixture and CCDC is then extracted from waterusing dichloromethane and is isolated by removing the extractant. Thisgives a powder whose crystal modification is not unambiguous. On thecontrary, the powder is largely amorphous and can contain mixtures ofdifferent crystal modifications. If, by chance, a uniform crystalmodification is formed, it is not clear how it can be extracted andobtained in a defined form. However, it is the precondition forpreparing medicaments that, for an active compound which can be presentin different crystal modifications, it can be stated unamibiguouslywhich of its crystal modifications is used for preparing the medicament.

The partially amorphous powder which is obtained by the preparationprocess outlined above is furthermore hygroscopic. However, amorphoussolids, and in particular hygroscopic solids, are difficult to handlewhen being processed pharmaceutically since, for example, they have lowbulk densities and unsatisfactory flow properties. Moreover, thehandling of hygroscopic solids requires special work techniques andapparatuses to obtain reproducible results, for example with respect tothe active compound content or the stability of the solid formulationsproduced.

It is therefore an object of the invention to prepare a crystaine formof a defined modification of CCDC which, owing to its physicalproperties, in particular its crystal properties, is easy to handle inpharmaceutical formulations.

This object is achieved according to the invention by a novelcrystalline form of CCDC which is referred to as modification Dhereinbelow.

The invention accordingly provides the crystalline modification D ofCCDC which is characterized in that it has an X-ray powder diffractogramwith the reflection signals (2 theta) of high and medium intensity (>30%relative intensity) listed in Table 1 below.

TABLE 1 X-ray powder diffractogram of CCDC of the modification D 2 θ (2theta) 7.6 9.5 12.8 14.2 17.5 19 19.3 19.5 20.4 21 21.8 22.6 25.2 27.5

BRIEF DESCRIPTION OF DRAWINGS

A characteristic X-ray powder diffractogram of the modification D ofCCDC is shown in FIG. 1.

A characteristic differential thermodiagram CCDC of the modification Dis shown in FIG. 2.

An infrared spectrum of CCDC of the modification D, measured in KBr, isshown in FIG. 3.

An X-ray powder diffractogram of the CCDC obtained by the ComparativeExample at page 5 is shown in FIG. 4.

An X-ray powder diffractogram of the CCDC obtained by Example 1 at page5, line 15-15 is shown in FIG. 5.

An X-ray powder diffractogram of a predominantly amorphous CCDC asreported at page 5, line 25-26 is shown in FIG. 6.

A characteristic differential thermodiagram of a predominantly amorphousCCDC as reported at page 5, line 25-26 is shown in FIG. 7.

Moreover, the CCDC modification D according to the invention differsfrom other forms of CCDC in a number of further properties. Theseproperties, on their own or together with the other parameters, may alsoserve for characterizing the CCDC modification D according to theinvention.

CCDC of the modification D is characterized by a melting point,determined with the aid of differential thermoanalysis (DTA), of from261° C. to 265° C. A characteristic differential thermodiagram is shownin FIG. 2.

CCDC of the modification D is characterized in that it has an infraredspectrum, measured in KBr, as shown in FIG. 3.

Crystal modification D of CCDC is obtained by dissolving CCDC of anunknown modification or amorphous CCDC at a concentration between 1 and3 per cent by weight in water, allowing the solution to stand until asolid precipitates out, filtering off this solid, drying the resultingwater-containing product, followed by heating to a temperature above therearrangement temperature.

The water-containing product can be dried by customary methods. Thus,the water-containing product can be dried, for example, at elevatedtemperature under reduced pressure. It is also possible to carry out thedrying in the presence of a customary drying agent, such as, forexample, phosphorus pentoxide.

The temperature required for rearranging the dried sample intomodification D can be determined by DTA of the dried substance. It isgenerally between 130° C. and 160° C.

CCDC of the crystal modification D is surprisingly stable and does notchange into another crystal modification or the amorphous form, even onprolonged storage. For these reasons, it is highly suitable forpreparing tablets or other solid formulations. Owing to its stability,it gives these formulations the desired long-lasting storage stability.Using the crystal modification D, it is therefore possible to prepare,in a defined and targeted manner, stable solid preparations of CCDC.

CCDC of the crystal modification D is highly active against pathogenicbacteria in the area of human or veterinary medicine. Its broad area ofuse corresponds to that of CCDC.

The X-ray powder diffractogram for characterizing the crystalmodification D of CCDC was obtained using a transmission diffractometerSTADI-P with a location-sensitive detector (PSD2) from Stoe.

The melting point of the differential thermoanalysis was obtained usingthe DSC 820 unit from Mettler-Toledo. Here, the sample of CCDC of thecrystal modification D was heated exposed to the atmosphere in analuminium crucible at 5 K/min.

The KBr IR spectrum was obtained using the 881 unit from Perkin-Elmer.The examples below illustrate the invention without limiting it. Thesolvent/base systems used in the examples below are particularlypreferred.

COMPARATIVE EXAMPLE

A mixture of 3.07 g of7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, 1.39 g of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane, 2.24 g of1,4-diazabicyclo[2.2.2]octane (DABCO), 29.5 ml dimethylformamide and29.5 ml of acetonitrile is stirred at room temperature for 16 hours. Thereaction mixture is concentrated at a bath temperature of 60° C. using arotary evaporator, and the residue is taken up in 10 ml of water. Theresulting solution is adjusted to pH 7 using dilute hydrochloric acid,and the solid is filtered off. The filtrate is extracted three timesusing 20 ml of dichloromethane each time. The organic phase is driedover sodium sulphate and filtered and the filtrate is concentrated at abath temperature of 60° C. using a rotary evaporator. This gives 2.4 gof a light-brown solid which has the X-ray powder diffractogram shown inFIG. 4 and is therefore predominantly amorphous.

EXAMPLE 1

1012 g of7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are initially charged in a mixture of 3300 ml of ethanol, 1980 mlof N-methyl-pyrrolidone and 534 g of Hünig base. The mixture is heatedunder reflux, and 459 g of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane arethen added dropwise. After the dropwise addition has ended, the mixtureis stirred under reflux for another 3 hours and then allowed to cool toroom temperature, and the solid is filtered off with suction and washedwith a total of 1800 ml of ethanol.

The resulting solid is suspended in a mixture of 4650 ml of ethanol and41 g of Hünig base, and the reaction mixture is heated under reflux for3 hours. The reaction mixture is allowed to cool again to roomtemperature, and the solid is filtered off with suction, washed with atotal of 1000 ml of EtOH and dried at from 60 to 70° C. in a vacuumdrying cabinet until the weight remains constant. This gives 1130 g of abeige solid which has the X-ray powder diffractogram shown in FIG. 5.

From 450 g of this solid and 29,450 g of doubly distilled water, a 1.5%strength (w/w) aqueous solution is prepared, which is filtered through a0.2 μm filter to remove any undissolved particles. This solution is thenstored at room temperature under exclusion of light in canisters ofpolyethylene for 4 weeks. After this period of time, the precipitatedsolid is filtered off through a 0.8 μm filter and dried at 75° C.overnight.

This gives 2 g of a solid which, according to X-ray powderdiffractogram, is predominantly amorphous (FIG. 6) and has the DTA shownin FIG. 7.

30 mg of the solid obtained in this manner are heated at 160° C. undernitrogen for 2 hours. This gives 28 mg of a solid which has the X-raypowder diffractogram shown in FIG. 1, the differential thermodiagramshown in FIG. 2 and the IR spectrum shown in FIG. 3.

What is claimed is: 1.8-Cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (CCDC) of the crystal modification D, characterized in that it hasan X-ray powder diffractogram with the following reflection signals (2theta) of high and medium intensity 2 θ (2 theta) 7.6 9.5 12.8 14.2 17.519 19.3 19.5 20.4 21 21.8 22.6 25.2 27.5

2.8-Cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (CCDC) of the crystal modification D, characterized in that it hasan X-ray powder diffractogram with the following reflection signals (2theta) of high and medium intensity 2 θ (2 theta) 7.6 9.5 12.8 14.2 17.519 19.3 19.5 20.4 21 21.8 22.6 25.2 27.5

and a melting point, determined by DTA, of from 261° C. to 265° C. 3.8-Cyano-1-cyclopropyl-7-(1,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic(CCDC) of the crystal modification D, obtainable by steps comprisingdissolving 1 to 3 percent by weight of CCDC of unknown modification oramorpnous CCDC in water, filtering of the solid which precipitates out,drying the solid and heating it to a temperature above rearrangementtemperature.
 4. Process for preparing CCDC of the modification D,characterized in that 1 to 3 percent by weight of CCDC of unknownmodification or amorphous CCDC is dissolved in water, and the solidwhich precipitates out is filtered off, dried and heated to atemperature above the rearrangement temperature.
 5. A compositioncharacterized in that it comprises, in addition to customary auxiliariesand excipients, CCDC of the modification D according to claim
 1. 6. Amethod of preparing a composition of CCDC of the modification Daccording to claim 1 comprising formulating the CCDC of the modificationD.
 7. A process for treating bacterial infection comprisingadministering thereto antibacterial compositions of CCDC of themodification D according to claim
 1. 8. A composition characterized inthat it comprises, in addition to customary auxiliaries and excipients,CCDC of the modification D according to claim
 2. 9. A method ofpreparing a composition of CCDC of the modification D according to claim2 comprising formulating the CCDC of the modification D.
 10. A processfor treating bacterial infection comprising administering theretoantibacterial compositions of CCDC of the modification D according toclaim 2.